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Diet impacts human health, influencing body adiposity and the risk of developing cardiometabolic diseases. The gut microbiome is a key player in the diet-health axis, but while its bacterial fraction is widely studied, the role of micro-eukaryotes, including Blastocystis, is underexplored. We performed a global-scale analysis on 56,989 metagenomes and showed that human Blastocystis exhibits distinct prevalence patterns linked to geography, lifestyle, and dietary habits. Blastocystis presence defined a specific bacterial signature and was positively associated with more favorable cardiometabolic profiles and negatively with obesity (p < 1e-16) and disorders linked to altered gut ecology (p < 1e-8). In a diet intervention study involving 1,124 individuals, improvements in dietary quality were linked to weight loss and increases in Blastocystis prevalence (p = 0.003) and abundance (p < 1e-7). Our findings suggest a potentially beneficial role for Blastocystis, which may help explain personalized host responses to diet and downstream disease etiopathogenesis.
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Blastocystis , Dieta , Microbioma Gastrointestinal , Obesidad , Humanos , Blastocystis/metabolismo , Masculino , Femenino , Infecciones por Blastocystis , Adulto , Persona de Mediana Edad , Intestinos/parasitología , Intestinos/microbiología , Enfermedades Cardiovasculares/prevención & control , MetagenomaRESUMEN
The complex network of specialized cells and molecules in the immune system has evolved to defend against pathogens, but inadvertent immune system attacks on "self" result in autoimmune disease. Both genetic regulation of immune cell levels and their relationships with autoimmunity are largely undetermined. Here, we report genetic contributions to quantitative levels of 95 cell types encompassing 272 immune traits, in a cohort of 1,629 individuals from four clustered Sardinian villages. We first estimated trait heritability, showing that it can be substantial, accounting for up to 87% of the variance (mean 41%). Next, by assessing â¼8.2 million variants that we identified and confirmed in an extended set of 2,870 individuals, 23 independent variants at 13 loci associated with at least one trait. Notably, variants at three loci (HLA, IL2RA, and SH2B3/ATXN2) overlap with known autoimmune disease associations. These results connect specific cellular phenotypes to specific genetic variants, helping to explicate their involvement in disease.
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Citometría de Flujo/métodos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Enfermedades del Sistema Inmune/genética , Polimorfismo de Nucleótido Simple , Humanos , FenotipoRESUMEN
BACKGROUND: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. METHODS: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. RESULTS: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGTâA (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. CONCLUSIONS: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).
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Factor Activador de Células B/genética , Mutación INDEL , Lupus Eritematoso Sistémico/genética , Esclerosis Múltiple/genética , Autoinmunidad , Factor Activador de Células B/metabolismo , Estudios de Casos y Controles , Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Italia , Lupus Eritematoso Sistémico/inmunología , MicroARNs , Esclerosis Múltiple/inmunología , Fenotipo , Polimorfismo de Nucleótido Simple , Riesgo , Análisis de Secuencia de ARN , Transcripción GenéticaRESUMEN
Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10(-8)) were detected at TPO-rs11675434, ATXN2-rs653178, and BACH2-rs10944479 for TPOAb-positivity, and at TPO-rs11675434, MAGI3-rs1230666, and KALRN-rs2010099 for TPOAb levels. Individual and combined effects (genetic risk scores) of these variants on (subclinical) hypo- and hyperthyroidism, goiter and thyroid cancer were studied. Individuals with a high genetic risk score had, besides an increased risk of TPOAb-positivity (OR: 2.18, 95% CI 1.68-2.81, Pâ=â8.1×10(-8)), a higher risk of increased thyroid-stimulating hormone levels (OR: 1.51, 95% CI 1.26-1.82, Pâ=â2.9×10(-6)), as well as a decreased risk of goiter (OR: 0.77, 95% CI 0.66-0.89, Pâ=â6.5×10(-4)). The MAGI3 and BACH2 variants were associated with an increased risk of hyperthyroidism, which was replicated in an independent cohort of patients with Graves' disease (OR: 1.37, 95% CI 1.22-1.54, Pâ=â1.2×10(-7) and OR: 1.25, 95% CI 1.12-1.39, Pâ=â6.2×10(-5)). The MAGI3 variant was also associated with an increased risk of hypothyroidism (OR: 1.57, 95% CI 1.18-2.10, Pâ=â1.9×10(-3)). This first GWAS meta-analysis for TPOAbs identified five newly associated loci, three of which were also associated with clinical thyroid disease. With these markers we identified a large subgroup in the general population with a substantially increased risk of TPOAbs. The results provide insight into why individuals with thyroid autoimmunity do or do not eventually develop thyroid disease, and these markers may therefore predict which TPOAb-positives are particularly at risk of developing clinical thyroid dysfunction.
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Autoanticuerpos/genética , Enfermedad de Graves/genética , Enfermedad de Hashimoto/genética , Yoduro Peroxidasa/genética , Autoanticuerpos/aislamiento & purificación , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Enfermedad de Graves/patología , Enfermedad de Hashimoto/patología , Humanos , Yoduro Peroxidasa/inmunología , Factores de Riesgo , Tiroiditis Autoinmune , Tirotropina/metabolismoRESUMEN
Introduction: Disease-modifying therapies (DMTs) have been shown to improve disease outcomes in multiple sclerosis (MS) patients. They may also impair the immune response to vaccines, including the SARS-CoV-2 vaccine. However, available data on both the intrinsic immune effects of DMTs and their influence on cellular response to the SARS-CoV-2 vaccine are still incomplete. Methods: Here, we evaluated the immune cell effects of 3 DMTs on the response to mRNA SARS-CoV-2 vaccination by comparing MS patients treated with one specific therapy (fingolimod, dimethyl fumarate, or natalizumab) with both healthy controls and untreated patients. We profiled 23 B-cell traits, 57 T-cell traits, and 10 cytokines, both at basal level and after stimulation with a pool of SARS-CoV-2 spike peptides, in 79 MS patients, treated with DMTs or untreated, and 32 healthy controls. Measurements were made before vaccination and at three time points after immunization. Results and Discussion: MS patients treated with fingolimod showed the strongest immune cell dysregulation characterized by a reduction in all measured lymphocyte cell classes; the patients also had increased immune cell activation at baseline, accompanied by reduced specific immune cell response to the SARS-CoV-2 vaccine. Also, anti-spike specific B cells progressively increased over the three time points after vaccination, even when antibodies measured from the same samples instead showed a decline. Our findings demonstrate that repeated booster vaccinations in MS patients are crucial to overcoming the immune cell impairment caused by DMTs and achieving an immune response to the SARS-CoV-2 vaccine comparable to that of healthy controls.
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Vacunas contra la COVID-19 , COVID-19 , Dimetilfumarato , Clorhidrato de Fingolimod , Esclerosis Múltiple , SARS-CoV-2 , Humanos , COVID-19/inmunología , COVID-19/prevención & control , Masculino , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/tratamiento farmacológico , Femenino , SARS-CoV-2/inmunología , Vacunas contra la COVID-19/inmunología , Persona de Mediana Edad , Adulto , Clorhidrato de Fingolimod/uso terapéutico , Clorhidrato de Fingolimod/farmacología , Dimetilfumarato/uso terapéutico , Dimetilfumarato/farmacología , Inmunosupresores/uso terapéutico , Natalizumab/uso terapéutico , Linfocitos B/inmunología , Vacunación , Linfocitos T/inmunología , Citocinas/metabolismoRESUMEN
Fresh blood immunophenotyping by flow cytometry, based on the reliable simultaneous detection of several markers in a cell, is the method of choice to study the circulating human immune system. Especially in large and multicenter studies, high sample quality is difficult to achieve, and adequate collection and storage of samples with fine-tuned whole blood cryopreservation is mandatory. Here, we compared the quality of immunophenotypic data obtained from fresh blood with those obtained after five cryopreservation methods by quantifying the levels of 41 immune cell populations. They comprised B and T lymphocyte subsets and their maturation stages, as well as monocytes and granulocytes. Three methods used fixative solutions and two other methods used dimethyl sulfoxide solutions to preserve cell viability. The fixative methods prevented detection of markers critical for identification of B and T cell subsets, including CD27, CXCR3, and CCR6. The other two methods permitted reliable discrimination of most immune-cell populations in thawed samples, though some cell frequencies varied compared to the corresponding fresh sample. Of those two methods, the one preserving blood in media containing dimethyl sulfoxide produced results that were most similar to those with fresh samples.
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Criopreservación , Dimetilsulfóxido , Criopreservación/métodos , Fijadores , Citometría de Flujo/métodos , Humanos , InmunofenotipificaciónRESUMEN
Monitoring immune responses to SARS-CoV-2 vaccination and its clinical efficacy over time in Multiple Sclerosis (MS) patients treated with disease-modifying therapies (DMTs) help to establish the optimal strategies to ensure adequate COVID-19 protection without compromising disease control offered by DMTs. Following our previous observations on the humoral response one month after two doses of BNT162b2 vaccine (T1) in MS patients differently treated, here we present a cross-sectional and longitudinal follow-up analysis six months following vaccination (T2, n=662) and one month following the first booster (T3, n=185). Consistent with results at T1, humoral responses were decreased in MS patients treated with fingolimod and anti-CD20 therapies compared with untreated patients also at the time points considered here (T2 and T3). Interestingly, a strong upregulation one month after the booster was observed in patients under every DMTs analyzed, including those treated with fingolimod and anti-CD20 therapies. Although patients taking these latter therapies had a higher rate of COVID-19 infection five months after the first booster, only mild symptoms that did not require hospitalization were reported for all the DMTs analyzed here. Based on these findings we anticipate that additional vaccine booster shots will likely further improve immune responses and COVID-19 protection in MS patients treated with any DMT.
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COVID-19 , Esclerosis Múltiple , Vacuna BNT162 , COVID-19/prevención & control , Vacunas contra la COVID-19 , Estudios Transversales , Clorhidrato de Fingolimod/uso terapéutico , Estudios de Seguimiento , Humanos , Esclerosis Múltiple/tratamiento farmacológico , SARS-CoV-2 , VacunaciónRESUMEN
OBJECTIVE: Animal models and clinical studies suggest that brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of depression. We test whether serum and plasma levels of BDNF are associated with trait neuroticism and its facets and with state measures of depressive symptoms. METHODS: In a community-based cohort (N = 2099), we measured serum and plasma BDNF concentrations and administered the Revised NEO Personality Inventory and the Center for Epidemiological Studies Depression Scale. Covariates included age, sex, cigarette smoking, obesity, and antidepressant use. RESULTS: Serum BDNF concentrations were inversely related to neuroticism (r = -0.074, p < .001), in particular the depression facet (r = -0.08, p < .001). Lower BDNF concentrations were also associated with severe depressive symptoms (Center for Epidemiological Studies Depression Scale ≥ 28; odds ratio = 0.906; 95% confidence interval = 0.851-0.965). The association of serum BDNF with neuroticism was independent of depressive symptoms, indicating that serum BDNF might represent a biological correlate of neuroticism and not just of transient depressive states. Plasma BDNF was not associated with measures of depression. CONCLUSIONS: Our study suggests that lower serum BDNF is associated with both a dispositional vulnerability to depression and acute depressive states in the general population.
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Factor Neurotrófico Derivado del Encéfalo/sangre , Depresión/sangre , Trastornos Neuróticos/sangre , Enfermedad Aguda , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Factor Neurotrófico Derivado del Encéfalo/antagonistas & inhibidores , Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Depresión/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Neuróticos/complicaciones , Factores Sexuales , Adulto JovenRESUMEN
Objectives: Vaccination against COVID-19 is highly recommended to patients affected by multiple sclerosis (MS); however, the impact of MS disease-modifying therapies (DMTs) on the immune response following vaccination has been only partially investigated. Here, we aimed to elucidate the effect of DMTs on the humoral immune response to mRNA-based anti-SARS-CoV-2 vaccines in MS patients. Methods: We obtained sera from 912 Sardinian MS patients and 63 healthy controls 30 days after the second dose of BNT162b2 vaccine and tested them for SARS-CoV-2 response using anti-Spike (S) protein-based serology. Previous SARS-CoV-2 infection was assessed by anti-Nucleocapsid (N) serology. Patients were either untreated or undergoing treatment with a total of 13 different DMTs. Differences between treatment groups comprised of at least 10 patients were assessed by generalized linear mixed-effects model. Demographic and clinical data and smoking status were analyzed as additional factors potentially influencing humoral immunity from COVID-19 vaccine. Results: MS patients treated with natalizumab, teriflunomide, azathioprine, fingolimod, ocrelizumab, and rituximab showed significantly lower humoral responses compared to untreated patients. We did not observe a statistically significant difference in response between patients treated with the other drugs (dimethyl fumarate, interferon, alemtuzumab and glatiramer acetate) and untreated patients. In addition, older age, male sex and active smoking were significantly associated with lower antibody titers against SARS-CoV-2. MS patients previously infected with SARS-CoV-2 had significantly higher humoral responses to vaccine than uninfected patients. Conclusion: Humoral response to BNT162b2 is significantly influenced by the specific DMTs followed by patients, as well as by other factors such as previous SARS-CoV-2 infection, age, sex, and smoking status. These results are important to inform targeted strategies to prevent clinically relevant COVID-19 in MS patients.
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Antirreumáticos/uso terapéutico , Vacuna BNT162/inmunología , COVID-19/prevención & control , Inmunogenicidad Vacunal/efectos de los fármacos , Esclerosis Múltiple/tratamiento farmacológico , Adulto , Anticuerpos Antivirales/inmunología , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , SARS-CoV-2 , Seroconversión/efectos de los fármacosRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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We report on the influence of ~22 million variants on 731 immune cell traits in a cohort of 3,757 Sardinians. We detected 122 significant (P < 1.28 × 10-11) independent association signals for 459 cell traits at 70 loci (53 of them novel) identifying several molecules and mechanisms involved in cell regulation. Furthermore, 53 signals at 36 loci overlapped with previously reported disease-associated signals, predominantly for autoimmune disorders, highlighting intermediate phenotypes in pathogenesis. Collectively, our findings illustrate complex genetic regulation of immune cells with highly selective effects on autoimmune disease risk at the cell-subtype level. These results identify drug-targetable pathways informing the design of more specific treatments for autoimmune diseases.
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Enfermedades Autoinmunes/genética , Autoinmunidad/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/epidemiología , Enfermedades Autoinmunes/patología , Humanos , Italia/epidemiología , Fenotipo , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
CD4+ regulatory T cells have been intensively studied during aging, but little is still known about age-related changes of other regulatory T cell subsets. It was, therefore, the goal of the present study to analyze CD8+human leukocyte antigen-antigen D related (HLADR)+ T cells in old age, a cell population reported to have suppressive activity and to be connected to specific genetic variants. We demonstrate a strong increase in the number of CD8+HLADR+ T cells with age in a cohort of female Sardinians as well as in elderly male and female persons from Austria. We also show that CD8+HLADR+ T cells lack classical activation molecules, such as CD69 and CD25, but contain increased numbers of checkpoint inhibitory molecules, such as cytotoxic T lymphocyte-associated antigen 4, T cell immunoglobulin and mucin protein-3, LAG-3, and PD-1, when compared with their HLADR- counterparts. They also have the capacity to inhibit the proliferation of autologous peripheral blood mononuclear cells. This suppressive activity is, however, decreased when CD8+HLADR+ T cells from elderly persons are analyzed. In accordance with this finding, CD8+HLADR+ T cells from persons of old age contain lower percentages of checkpoint inhibitory molecules than young controls. We conclude that in spite of high abundance of a CD8+ regulatory T cell subset in old age its expression of checkpoint inhibitory molecules and its suppressive function on a per cell basis are reduced. Reduction of suppressive capacity may support uncontrolled subclinical inflammatory processes referred to as "inflamm-aging."
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Envejecimiento/inmunología , Inflamación/inmunología , Linfocitos T Reguladores/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/metabolismo , Austria , Antígenos CD8/metabolismo , Antígeno CTLA-4/metabolismo , Proliferación Celular , Estudios de Cohortes , Femenino , Antígenos HLA-DR/metabolismo , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Humanos , Tolerancia Inmunológica , Italia , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/metabolismo , Adulto Joven , Proteína del Gen 3 de Activación de LinfocitosRESUMEN
OBJECTIVES: Lower levels of serum brain derived neurotrophic factor (BDNF) is one of the best known biomarkers of depression. To identify genetic variants associated with serum BDNF, we tested the Val66Met (rs6265) functional variant and conducted a genome-wide association scan (GWAS). METHODS: In a community-based sample (N = 2054; aged 19-101, M = 51, SD = 15) from Sardinia, Italy, we measured serum BDNF concentration and conducted a GWAS. RESULTS: We estimated the heritability of serum BDNF to be 0.48 from sib-pairs. There was no association between serum BDNF and Val66Met in the SardiNIA sample and in a meta-analysis of published studies (k = 13 studies, total n = 4727, P = 0.92). Although no genome-wide significant associations were identified, some evidence of association was found in the BDNF gene (rs11030102, P = 0.001) and at two loci (rs7170215, P = 4.8 × 10â»5 and rs11073742 P = 1.2 × 10â»5) near and within NTRK3 gene, a neurotrophic tyrosine kinase receptor. CONCLUSIONS: Our study and meta-analysis of the literature indicate that the BDNF Val66Met variant is not associated with serum BDNF, but other variants in the BDNF and NTRK3 genes might regulate the level of serum BDNF.